Arctigenin Exerts Antidepressant-and Anxiolytic-like Effects In Adult Mice

Objective: Depression is an affective disorder with major depressive episodes,thinking retardation,and decreased will-behaviors.Most of antidepressants used in clinics exert many significant limitations;such as low efficiency,delayed onset,and large side effects.Finding new safe and potential antidepressant drug ingredients is of great interest in the field of depression research.Arctigenin(ARC)is the main pharmacological active part of Arctium,a traditional Chinese medicine.Series of evidence reported that arctigenin could exert antibacterial,anti-inflammatory,antiviral,and enhance immune response.Recent studies have confirmed that ARC treatment could improve cognition and antagonize oxidative stress injuries in the central nervous systems,suggesting that arctigenin has the potential neuroprotective effects.It's worth noting that no evidence has been reported to investigate the potential roles of arctigenin in nerve injury and even stress-related neurobehaviors,such as depression and anxiety.In the present study,acute stress and chronic mild stress(CMS)mice models were used to clarify the potential effects of arctigenin treatment on depressive-and anxiety-like behaviors induced by stress and the underlying mechanism,mainly focused on vascular genesis related proteins,angiogenin(ANG),thrombopoietin(TPO),and vascular endothelial growth factor(VEGF).Methods: 80 ICR mice were used in the present study.mice in acute stress models were divided into 3 groups: vehicle group,arctigenin 10mg/kg,30 mg/kg.Behavioral tests were performed after intraperitoneal injection daily for 14 consecutive days,open field test(OFT),novelty suppressed feeding(NSF),were conducted to reflect anxiety-like behaviors and tail suspension test(TST),forced swimming test(FST),and sucrose preference test(SPT)were used to assess the depressive-like behaviors of mice.CMS procedure was used to further investigate the effects of ARC.Mice were randomly divided into naive group and CMS group.Mice in the CMS group were randomly divided into 4 groups and received a28-dstress treatment.From the 14 th day,mice were treated with vehicle,arctigenin(10,30 mg/kg)and fluoxetine(10 mg/kg)for 14 continuous days.Behavioral tests were performed 24 h after the last drug treatment.Behavioral tests were carried out similar to that of the acute stress mice procedure.ELISA: After the last behavioral test,blood samples were collected through the eyeballs of the mice and serum was gained and stored at-80°C.Concentration of serum levels of ANG,VEGF,and TPO were detected by ELISA kits according to the instruction.Results: Results from behavioral tests showed that ARC pretreatment exerted significant antidepressant-and anxiolytic effects in mice exposed to acute stress.Reflected by the increased sucrose preference in the SPT(P < 0.05),decreased immobility time in both FST and TST(P < 0.05),increased time spent in center zone time and crossing activity in the OFT(P < 0.05),and decreased latency to feeding in the NSF(P < 0.05).Behavioral results from CMS-treated mice of showed that a 28 d CMS treatment induced significant depressive-and anxiety-like behaviors,which could be significantly reversed by repeated ARC treatment.ARC treatment could significantly increase the decreased sucrose preference in the SPT(P < 0.05)and decrease of floating time in the FST(P < 0.05)of mice exposed to CMS.The decreased time spent in center zone and crossing activities in the OFT(P < 0.05)and the prolonged latency to feeding in the NSF of CMS-treated mice were also significantly blocked by ARC treatment,compared with that of mice with vehicle-treatment(P < 0.05).The ELISA results showed that arctigenin treatment significantly increased the serum concentration of ANG(P < 0.05),TPO(P < 0.01)and VEGF(P < 0.01)of mice exposed to acute stress,compared with that of mice in vehicle group.CMS treatment induced decreased serum levels of ANG(P < 0.01),but decreased the serum concentration of TPO(P < 0.01).Arctigenin intervention could reversed the alteration of serum levels of ANG(P < 0.05)and TPO(P < 0.01),compared with that of mice in the vehicle group.Conclusions:1 Arctigenin can prevent acute stress,CMS-induced depressive,and anxiety-like behaviors in mice.2 Antidepressant and anxiolytic-like effects of arctigenin may be associated with its regulatory effects on serum levels of ANG,TPO,and VEGF.